HIV-infected persons have an increased incidence of emphysema compared to those without HIV infection, and it has been hypothesized that this accelerated disease progression is the result of one or more latent infectious agents that amplify the pulmonary inflammatory response to cigarette smoke. Pneumocystis jirovecii (formerly Pneumocystis carinii, f. sp. Hominis) is one infectious agent that likely plays a key role in the development of HIV-infected smokers are particularly susceptible to Pneumocystis colonization regardless of CD4 cell count or use of prophylaxis. Pneumocystis colonization is also increased in non-HIV-infected patients with chronic obstructive pulmonary disease (COPD) and is directly related to the severity of the disease. The presence of Pneumocystis in the lungs, even at low levels as seen in colonization, produces inflammatory changes similar to those seen in COPD, with increases in the numbers of neutrophils and cytotoxic CD8+ lymphocytes. We hypothesize that Pneumocystis accelerates emphysema in HIV-infected smokers by stimulating inflammation and tissue destruction. We will explore this theory by completing the following specific aims: 1) Testing the hypothesis that Pneumocystis colonization contributes to HIV-associated emphysema by stimulating pulmonary inflammation and release of proteases. 2) Testing the role of Pneumocystis colonization in accelerating progression of physiologic obstruction or the anatomic airway and parenchymal changes associated with emphysema in HIV-infected patients. 3) Testing the effects of treatment of Pneumocystis colonization on decreasing inflammation and protease activity. We will study a cohort of HIV-infected smokers and non-smokers and perform detailed analyses of pulmonary inflammation and Pc colonization which will be correlated to functional outcomes of pulmonary physiology and therapy of HIV-associated emphysema and provide a model for emphysema in the general population. Public health significance: This proposal will explain why HIV-infected individuals develop emphysema faster than non-HIV-infected people. This information will help us understand and treat emphysema in these patients and in the many non-HIV-infected people who suffer from this disease.